Liquid pharmaceutical composition for the delivery of active ingredients

ABSTRACT

The invention provides novel pharmaceutical compositions based on semifluorinated alkanes which are useful as carriers for a broad range of active ingredients. Preferred active ingredients include poorly water-soluble and/or hydrolytically sensitive drug substances. The compositions are designed as suspensions and have superior physical properties which make them highly useful as pharmaceutical delivery systems. The compositions may be administered topically into the eye, or injected via the subcutaneous or intramuscular route. The invention further provides kits comprising such compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/658,187, filed on Jul. 24, 2017, which is a continuation of U.S.application Ser. No. 13/824,048, filed on Mar. 15, 2013, which is aNational Stage Entry under 35 U.S.C. § 371 claiming benefit of PCTApplication No. PCT/EP2011/068141, filed on Oct. 18, 2011, which claimspriority from European Application No. 10188242.1, filed Oct. 20, 2010,the contents of each of which are hereby incorporated by reference intheir entireties.

DESCRIPTION Background

The present invention relates to pharmaceutical compositions in liquidform which are suitable for the delivery of active ingredients usingvarious routes of administration, in particular injection or topicaladministration into the nose, an ear, or an eye of a patient.

Pharmaceutical compositions in liquid form represent one of thepreferred types of drug formulations. In the context of oralpharmacotherapy, liquid formulations are important for patients who havedifficulties swallowing tablets, capsules or other solid dosage forms,such as children or elderly patients, or when substantial dosingflexibility is required. Certain topical routes of administration, suchas nasal, otic, or ophthalmic administration, typically require theliquid form in order to provide for an efficient delivery of the activeingredient and a patient-friendly mode of use. Moreover, injectable drugproducts are mostly in liquid form as the injection or infusion ofliquids is particularly convenient and flexible compared to otherparenteral dosage forms.

The most simple type of liquid formulation is a solution, such as anaqueous solution of the active pharmaceutical ingredient. In certaincases, however, the development of a more complex formulation such as asuspension may be considered.

For example, if a drug substance is very poorly soluble in aqueous orother biocompatible solvent systems, or if it is hydrolytically labile,a simple solution may not be feasible or represent the best choice.Another occasional motivation to formulate a drug suspension is in orderto achieve a prolonged pharmacological effect by slow dissolution anduptake of the active ingredient.

Examples of pharmaceutical suspensions for nasal use include Avamys®(active ingredient: fluticasone furoate), Nasonex® (active ingredient:mometasone furoate), and Pulmicort® Topinasal (active ingredient:budesonide). An ophthalmic suspension that has reached the market stageis, for example, Livocab® (active ingredient: levocabastine). Among thecommercial suspension formulations for injection are Humalog® (activeingredient: insulin lispro), Tardocillin® for injection (activeingredient: benzathine benzylpenicillin), as well as most vaccines.

Common problems associated with pharmaceutical suspensions are usuallyrelated to physical stability issues, potential irritability, and/ormanufacturing challenges. Obviously, suspensions are prone to physicalchanges of various types, all of which may have impact on drug productquality and performance.

For example, suspended particles may flotate or sediment, depending ontheir density relative to that of the liquid phase in which they aredispersed. Along with flotation or sedimentation, the suspendedparticles may aggregate, and depending on the forces by which theparticles attract each other, the aggregates thus formed may be ratherdifficult to resuspend. A further problem is that in suspensions havingnon-uniform particle sizes there is a tendency for smaller particles togradually dissolve, whereas larger particles grow through the depositionof dissolved material onto their surfaces (Ostwald ripening). In result,the particle size distribution of a suspension may become broader overtime. Particles which grow beyond a certain size may be unsuitable forthe intended use; for example, they may occlude an injection cannula or,in case of ophthalmic administration, irritate or even damage the ocularsurface.

In general, suspensions of particles have a somewhat higher risk ofirritating or damaging certain issues simply by their physical presence.This is true for parenteral injection where suspended particles wouldbring about the risk of embolic events in the vasculature in case ofinjection into the bloodstream, for which reason suspensions forintravenous use are normally discouraged, unless it can be assured thatall particles are in the low micron or submicron size range and thus notembolic. But also for intradermal, subcutaneous or intramuscularinjection it has been found that suspended particles above a certainparticle size may lead to some—typically mild—irritation at theinjection site, especially of the injected amount of material isrelatively large.

Neither is it straightforward to manufacture a pharmaceutical suspensionin a highly reproducible manner as is required in particular fornon-oral products. If the particle size and the distribution thereof iscritical, which is likely in the case of a parenteral suspension, but tosome degree also for an ophthalmic suspension, significant processengineering efforts may be required in order to ensure thereproducibility of the physical properties of the formulation. Moreover,if the product is required to be sterile, which is always the case foran injectable or ophthalmic product, heat sterilisation will normally beextremely difficult in view of the major physical changes which theproduct undergoes during heating, and sterile filtration which istypically performed with products that cannot be heat sterilised will begenerally unfeasible. The remaining options include aseptic processing,which is technically complex and challenging, and gamma sterilisation,which may be feasible depending on the chemical stability of the drugsubstance and of the excipients.

Drug products for the treatment of ophthalmic diseases or conditions aremostly formulated as liquid compositions for local administration. Fourophthalmic target sites for drugs may be differentiated: (a) theconjunctiva, the eye lids, and other structures of the front of the eye;(b) the cornea; (c) the anterior and posterior chamber and theirassociated structures; and (d) the vitreous cavity (NM Davies, Clin.Exper. Pharmacol. Physiol. 27, 558-562, 2000). Except for the vitreouscavity or body, these targets may be reasonably reached by manytherapeutic compounds when administered as eye drops or ointments. Incontrast, if the vitreous body is the target, it may be difficult toobtain therapeutic drug concentrations after local topicaladministration, and systemic or intravitreal administration aretypically preferred. For the other targets, the benefits of non-invasivelocal administration are similar to other topical routes, in particularin that it provides an opportunity to achieve therapeutic drugconcentrations at the site of action while minimising the amount of drugin the systemic circulation.

At the same time, achieving local bioavailability of a drug at anophthalmic target site after topical administration is complicated byseveral anatomical and physiological factors. A requirement foreffective delivery is that a drug formulation introduced to thepre-ocular area must be retained at this site for a sufficient time inorder to allow for the uptake of the drug by the respective tissues. Aproblem of this route of administration is that the normal amount ofliquid (tear fluid) present in this region is about 7 μl, most of whichresides in the conjunctival sac, while some covers the cornea. Theaddition of fluid is possible, but probably the holding capacity of thefront of an eye is limited to about 30 μl (NM Davies, ibid.).Considering the fact that aqueous eye drops usually have a volume in theregion of 50 μl per drop, this illustrates that large fractions ofadministered drug will normally be lost immediately upon administrationthrough spillage or overflow. Subsequently, drug will be eliminated fromthe site of administration via the continuous physiological turnover oftear fluid, which occurs at a rate of approx. 1 μl—or about 16%—perminute. These two rapid clearance mechanisms can make the effectivelocal delivery of those drugs rather challenging which are taken up onlyslowly.

If the target site is the cornea itself, or the anterior or posteriorchamber, intraocular absorption from the site of administration at thefront of the eye is required. It is believed that the major route ofabsorption into the eye is through the cornea (I Ahmed, Int. J. Pharm.38, 9-21, 1987). As the cornea is rather small in its surface area andpoorly permeable in comparison with the vascularised conjunctiva, theabsorption into the eye is generally not very efficient and leads tointraocular bioavailabilities in the range of only 1-10%. The poorpermeability results from the structure of the cornea, which in essencecomprises three layers: the outer epithelium, the stroma, and the innerendothelium. Due to the hydrophilic nature of the stroma and thelipophilic epithelial layers, the cornea presents an effective diffusionbarrier to both lipophilic and hydrophilic compounds.

Nevertheless, topical ophthalmic delivery, while not highly efficient inabsolute terms, is still relatively effective for many small moleculardrugs, and acceptable to patients in terms of convenience. As mentioned,most ophthalmic drug products are presented as eye drops or ointmentsfor topical administration. While most of the eye drop formulations areaqueous solutions, the properties of certain drug substances, inparticular in terms of solubility and/or hydrolytic instability, presentsubstantial challenges for this type of formulation, so that ophthalmicsuspensions remain to be an important alternative to solutions, in spiteof their problems as discussed above.

As an alternative to aqueous preparations, oily eye drops may beformulated if the respective drug substance is poorly water-soluble orprone to hydrolytic degradation. However, one of the major disadvantagesof all oil-based formulations for ophthalmic administration is that theyinherently have a negative impact on vision. Whether used as oilysolutions or oil-in-water emulsions, they exhibit a refractive indexwhich differs substantially from that of physiological tear fluid, whichleads to visual disturbances and blurring.

Moreover, oil-based formulations do not readily mix with tear fluid toform a homogenous liquid phase. Oily solutions are altogether immisciblewith the aqueous tear fluid, and the exact fate of an emulsion mixedwith tear fluid in a physiological setting is not completelypredictable.

Oil-in-water emulsions of poorly water-soluble drugs like ciclosporinfurther exhibit the disadvantage that they have a limited drug loadcapacity. While the active ingredient may have some solubility in theoil phase, this phase is only dispersed in the coherent aqueous phase ofthe emulsion so that the maximum overall drug concentration in theformulation is very limited.

In contrast to single phase systems such as aqueous or oily solutions,oil-in-water emulsions are also more complex and difficult tomanufacture, especially in sterile form. Frequently, emulsions are notreadily sterilisable by thermal treatment without negative impact on thephysical properties of the emulsion. On the other hand, asepticprocessing is complex, costly, and is associated with higher risks offailure, i.e. microbial contamination of the product.

Furthermore, oil-in-water emulsions are like aqueous solutions prone tomicrobial contamination during use. If they were to be presented inmulti-dose containers which are in principle more cost-efficient andconvenient for patients than single-use vials, they would have to bepreserved in order to ensure their microbiological quality. At the sametime, preservatives which can be used in ophthalmic formulations arepotentially damaging to the eye, in particular to the ocular surface,and should be avoided whenever possible.

As another alternative to aqueous liquid carriers which are problematicfor water-sensitive drug substances, U.S. Pat. No. 6,458,376 proposeseye drops on the basis of non-aqueous liquid perfluorocarbons. At leastsome of the preferred perfluorocarbons are presented as biocompatibleand non-irritating to the eye. The compositions are formulated assuspensions, in particular of polymeric carrier particles which includethe drug substance and which are capable of releasing the drug slowlyover an extended period of time. Moreover, the compositions may comprisea surfactant such as a non-ionic ethoxylated alcohol or sorbitan. Thesurfactant functions as a suspension stabiliser and preventsaggregation.

However, it has been found by the present inventors that these drugsuspensions in perfluorocarbons suffer from various disadvantages. Ifformulated without surfactant, they tend to separate (by flotation, orsometimes by sedimentation) very rapidly, and lead to substantialparticle aggregation. At the same time, the settled suspensions are verydifficult to redisperse by shaking alone. These poor physical suspensionproperties would seriously impact their usefulness as eye drops. Notonly is vigorous shaking and the need for rapid administration beforethe suspension separates again very inconvenient to patients; poorsuspension properties are also associated with the risk of substantialdosing errors. On the other hand, surfactants, which are potentiallyirritating to the eye and whose use in ophthalmic preparations should beavoided or limited to a low level, are not very effective in stabilisingperfluorocarbon suspensions. The incorporation of high amounts ofsurfactant which may achieve a better stabilisation of the suspensionsystem is physiologically undesirable.

In the context of aerosol delivery of lung surfactant, WO 2005/099718mentions that semifluorinated alkanes such as perfluorooctylethane orperfluorohexyldecane may be used as liquid carriers of surfactantsubstitutes, for example native or synthetic phospholipids. The documentis silent about the delivery of poorly soluble or chemically instabledrug substances, let alone for the purpose of topical administration tothe nose or eye, or by injection. Neither does it disclose any othersystems beyond colloidal solutions of surfactants.

There is a need for further improvements in the formulation ofpoorly-soluble or water-sensitive drugs. In particular, there is a needfor liquid drug formulations which are suitable for the ophthalmic,injectable, and/or other routes of administration and which do notpossess one or more of the disadvantages of prior art compositions.There is also a need for improved suspension formulations which arephysically stable and easy to handle, as well as improved non-aqueousformulations for hydrolytically sensitive drug substances.

It is therefore an object of the present invention to provide a novelpharmaceutical composition which is useful for the delivery ofpoorly-soluble and/or water-sensitive drug substances. Another object isto provide improved formulations for topical ophthalmic delivery whichovercome one or more disadvantages of known formulations. It is also anobject to provide further improved composition which may be deliveredvia the injectable route. Moreover, it is an object to providepharmaceutical suspensions with improved suspension properties. Afurther object is to provide improved non-aqueous liquid formulationswhich overcome the limitations of presently known formulations. Furtherobjects of the invention will become clear on the basis of the followingdescription, examples, and patent claims.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition which is inthe form of a suspension and comprises particles of an active ingredientand a liquid vehicle. The vehicle is characterised in that it comprisesa semifluorinated alkane.

The active ingredient which is suspended in the vehicle is preferablyselected from drug substances which are poorly water-soluble, orsensitive to hydrolytic degradation, or both. The active ingredient ispresent in a therapeutically effective amount.

The composition of the invention is particularly suitable for thedelivery of such preferred drug substances via the topical route ofadministration, in particular by topical administration to the eye ornose of a patient. It is also useful as an injectable medicine.

It has been found by the inventors that the composition of the inventionsurprisingly overcomes several drawbacks of previously known aqueous andnon-aqueous suspension formulation. In particular, it does not easilyagglomerate, and it is readily redispersed homogeneously by simpleshaking. Moreover, these advantageous physical properties which allowconvenient administration and ensure precise and reproducible dosing aretypically achieved without the incorporation of surfactants, or withvery low surfactant levels which are unlikely to irritate the eye, nose,or the site of injection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Particle size distributions of suspensions of ciprofloxacin inF6H8 and PFO.

FIG. 2: Particle size distributions of suspensions of levofloxacin inF6H6, F6H8 and PFO.

FIG. 3: Images of ciprofloxacin/F6H8 and ciprofloxacin/PFO suspensionsat 0 to 30 minutes after shaking.

FIG. 4: Images of levofloxacin/F6H6, levofloxacin/F6H8, andlevofloxacin/PFO suspensions at 0 to 30 minutes after shaking.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides a pharmaceuticalcomposition which is in the form of a suspension and comprises particlesof an active ingredient, which is present in a therapeutically effectiveamount, and a liquid vehicle. The vehicle is characterised in that itcomprises a semifluorinated alkane of the formula RFRH, wherein RF is alinear perfluorinated hydrocarbon segment with 3 to 10 carbon atoms andwherein RH is a linear alkyl group with 3 to 10 carbon atoms.

As used herein, a pharmaceutical composition is a composition comprisingat least one pharmacologically active ingredient or diagnostic agent incombination with at least one pharmaceutical excipient. Atherapeutically effective amount refers to a dose, concentration orstrength which is useful for producing a desired pharmacological effect.

A suspension may be defined as a type of a dispersion, i.e. a systemhaving at least one continuous (or coherent) phase and at least onediscontinuous (or inner) phase which is dispersed in the continuousphase. In a suspension, the dispersed phase is in the solid state. Thesuspensions useful for practising the invention are liquids, at least atphysiological temperature, which means that the continuous phase is aliquid. Typically, the suspensions are also liquid at room temperature.

Some of the key advantages of the present invention are brought about bythe presence of a semifluorinated alkane in the composition, functioningas a liquid suspension vehicle. Semifluorinated alkanes are linear orbranched alkanes some of whose hydrogen atoms have been replaced byfluorine. In the semifluorinated alkanes (SFA's) used in the presentinvention, one linear non-fluorinated hydrocarbon segment and one linearperfluorinated hydrocarbon segment are present, each having from 3 to 10carbon atoms. These compounds thus follow the general formulaF(CF₂)_(n)(CH₂)_(m)H, wherein n and m are independently selected fromthe range of 3 to 10.

A nomenclature which is frequently used for SFA's designates aperfluorated hydrocarbon segment as RF and a non-fluorinated segment asRH. Alternatively, the compounds may be referred to as FnHm and FnHm,respectively, wherein F means a perfluorated hydrocarbon segment, Hmeans a non-fluorinated segment. Again, n and m define the number ofcarbon atoms of the respective segment. For example, F3H3 is used forperfluoropropylpropane. Moreover, this type of nomenclature is usuallyused for compounds having linear segments. Therefore, unless otherwiseindicated, it should be assumed that F3H3 means1-perfluoropropylpropane, rather than 2-perfluoropropylpropane,1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.

SFA's which are useful in the context of the present invention are alsodescribed in EP-A 965 334, EP-A 965329 and EP-A 2110126, the disclosureof which documents is incorporated herein by reference.

Preferred SFA's include in particular the compounds F4H5(1-perfluorobutylpentane), F4H6 (1-perfluorobutylhexane), F6H4(1-perfluorohexylbutane), F6H6 (1-perfluorohexylhexane), F6H8(1-perfluorohexyloctane), and F6H10 (1-perfluorohexyldecane).Particularly preferred for carrying out the invention are F4H5, F4H6,F6H6 and F6H8. In another particularly preferred embodiment, thecomposition of the invention comprises F6H8.

Optionally, the composition may comprise more than one SFA. It may beuseful to combine SFA's, for example, in order to achieve a particulartarget property such as a certain density or viscosity. If a mixture ofSFA's is used, it is furthermore preferred that the mixture comprises atleast one of F4H5, F4H6, F6H4, F6H6, F6H8, and F6H10, and in particularone of F4H5, F4H6, F6H6 and F6H8. In another embodiment, the mixturecomprises at least two members selected from F4H5, F4H6, F6H4, F6H6,F6H8, and F6H10, and in particular at least two members selected fromF4H5, F6H6 and F6H8.

Liquid SFA's are chemically and physiologically inert, colourless andstable. Their typical densities range from 1.1 to 1.7 g/cm³, and theirsurface tension may be as low as 19 mN/m. SFA's of the RFRH type areinsoluble in water but also somewhat amphiphilic, with increasinglipophilicity correlating with an increasing size of the non-fluorinatedsegment.

Liquid SFA's of the RFRH type are being used commercially for unfoldingand reapplying a retina, for long-term tamponade as vitreous humorsubstitute (H. Meinert et al., European Journal of Ophthalmology, Vol.10(3), pp. 189-197, 2000), and as wash-out solutions for residualsilicon oil after vitreo-retinal surgery. Experimentally, they have alsobeen used as blood substitutes (H. Meinert et al., Biomaterials,Artificial Cells, and Immobilization Biotechnology, Vol. 21(5), pp.583-95, 1993). These applications have established SFA's asphysiologically well tolerated compounds. On the other hand, SFA's havenot been used as excipients in approved drug products as of today.

It has been found by the inventors that SFA's are particularly suitableas carriers, vehicles or excipients in ophthalmic compositions fortopical administration. This is based on the fact that SFA's are capableof dissolving many poorly water-soluble compounds which are of interestin ophthalmology, but also on the discovery that they are unexpectedlywell-tolerated by the eye, as shown in preclinical testing. This is verysurprising as organic or non-aqueous solvents, perhaps with theexception of oily compounds, are typically very irritating or evenhighly damaging when administered topically to an eye.

Compared to oily carriers or vehicles in ophthalmic compositions fortopical use, SFA's exhibit a refractive index which is much bettercompatible with the aim of a minimally affected vision: While oilypreparation lead to a blurry vision and can therefore not beadministered in any situation in which the patient needs a clear vision,SFA's cause little or no blurring.

TABLE 1 SFA Refractive index F4H4 1,308 F4H5 1,3204 F4H6 1,334 F4H71,3357 F4H8 1,348 F6H4 1,306 F6H6 1,3224 F6H7 1,3366 F6H8 1,3432 F6H91,3494

By illustration, the refractive index of tear fluid is close to that ofwater, i.e. 1.333 at room temperature (RT). Oils typically have asubstantially higher refractive index such as about 1.46 (peanut oil),1.47 (sesame oil), or 1.48 (castor oil). In contrast, the inventors havedetermined the refractive indices of various SFA's of interest to be inthe region of 1.29 to 1.35, i.e. much closer to that of water. In one ofthe specific embodiments, the invention is therefore practised with anSFA whose refractive index is from 1.29 to 1.35, and in particular fromabout 1.30 to about 1.35 at 20° C. The refractive index for selectedSFA's is shown in table 1.

Compared to the perfluorocarbons proposed as vehicles for ophthalmicmedicines in e. g. U.S. Pat. Nos. 5,518,731 and 6,458,376, the SFA'sprovided by the present invention allow the formulation of liquidsuspension with superior properties. It has been found by the inventorsthat when perfluorinated compounds are used as liquid vehicles, thesuspensions tend to separate very rapidly by flotation of the dispersedphase, or by its sedimentation, depending on the relative densities ofthe dispersed phase and of the continuous phase. This is accompanied bya rapid formation of particle aggregates which may be dense and poorlyredispersible. Rapid flotation or sedimentation makes precise andreproducible dosing very challenging, if not impossible. For example, ifan ophthalmic suspension settles very rapidly after shaking, the firstdosing from a full container, if not withdrawn immediately upon shaking,will contain a lower-than-intended number of drug particles, unless thecontainer is held upside down, in which case more than the intendedquantity of drug particles will be dispensed. When the same container isnearly empty and the last doses are dispensed, the drug dose withdrawnper volume will be too high if it was low in the beginning, and viceversa.

Moreover, aggregates may easily obstruct the dispensing channels oropenings of containers and thereby lead to erroneous dosings. Ifdispensed from the container, they may cause irritation of theconjunctiva or of the cornea, depending on their size, shape andhardness.

In contrast, the SFA-based suspensions according to the invention remainfinely dispersed and homogeneous. If flotation or sedimentation takesplace, it occurs slowly, leaving sufficient time for the patient towithdraw a dose after shaking the container. The formation of largeaggregates is not observed. After flotation or sedimentation, the drugparticles are easily redispersed by gentle shaking, and appear tolargely retain their original particle size distribution.

These unexpected properties of SFA-based suspensions result in superiorpharmaceutical quality and performance characteristics. The level ofconvenience to the patient and/or health care provider is greatlyincreased. More importantly, the dosing accuracy, i.e. precision andreproducibility of dosing, is greatly improved over other types ofpharmaceutical suspensions. This will bring about a more reliabletherapeutic effect and a reduced risk of adverse effects which resultfrom overdosing.

The superior physical properties of the suspensions according to theinvention render these compositions particularly useful for topicaladministration to the eye of a patient. However, similar benefits arealso achieved when the suspensions are administered nasally, into anear, or parenterally by injection. Preferred modes of injection includedermal, subcutaneous, intramuscular, and locoregional injection. Mostpreferred are the subcutaneous and intramuscular routes ofadministration.

Moreover, SFA's exhibit a remarkable wetting and spreading behaviour bywhich they deliver an incorporated active ingredient rapidly andeffectively to the corneal surface and conjunctiva. Wetting means theability of a liquid to establish and maintain contact with a solidsurface, resulting from intermolecular interactions when the two arebrought together. The balance between adhesive and cohesive forcesdetermines the degree of wetting. The higher the adhesive forcescompared to the cohesive forces, the more a drop of liquid will spreadacross the surface of the solid material. Conversely, very high cohesiveforces within the liquid will cause the drop to form a sphere, thusavoiding contact with the surface. Similarly, spreading may also occurat the interface of two liquids which are brought into contact with eachother.

A measure for wetting and spreading is the contact angle θ. The contactangle is the angle at which the liquid-vapour interface meets thesolid-liquid or liquid-liquid interface. The tendency of a drop tospread out increases as the contact angle decreases. Thus, the contactangle provides an inverse measure of wettability.

A low contact angle of less than 90° indicates high wettability and/orspreading, whereas a higher contact angle indicates poor wettability andspreading. Perfect wetting and spreading results in a contact angle of0°, also reported as no measurable contact angle.

The inventors have found that the SFA's used in the present invention,in particular the preferred SFA's, exhibit an excellent wetting ofvarious surfaces which are not easily wetted by conventional drugformulations. For example, the contact angle of both F4H5 and F6H8 ontablets compressed from either trospium chloride or fenofibrate (150 mgof drug substance compressed at 15-20 kN to tablets of 13 mm indiameter) was not measurable, i.e. perfect wetting occurred. It is notedthat fenofibrate is an example of a hydrophobic, poorly water-solublecompound, whereas trospium chloride is hydrophilic and water-soluble. Incomparison, the contact angle of purified water on the fenofibratetablet was determined as 92.5°, i.e. the tablet was poorly wetted bywater.

A further surprising advantage of SFA's found by the inventors is thatthey appear to form very small droplets when dispensed from a droppersuch as an eye dropper. Without wishing to be bound by theory, it isbelieved that the small droplet size is a result of an interplay of theSFA's unique properties in terms of their density, viscosity, andsurface tension. In any case, it is believed that for topicaladministration into an eye a small drop or volume of administration ishighly advantageous as the capability of the lacrimal sac to accept andhold fluid is extremely limited. In fact, it is very common that theadministration of a conventional eye drop formulation based on water oroil immediately leads to a discharge of a substantial fraction of theadministered medicine as well as some tear fluid. At the same time,there is a risk that some of the administered dose will be taken upsystemically via the nasolacrimal duct. Hence, if an effective dose ofan active ingredient can be incorporated in a small volume of liquidwhich can be dispensed as a very small droplet, this should alsocontribute to a substantially increased dosing reliability andreproducibility, thus enhancing the safety and effectiveness of thetherapy.

A yet further advantage of the invention which is based on the use ofSFA's is that they can be designed or mixed for an optimally adjustedevaporation behaviour after administration. Thus it is possible toformulate an ophthalmic composition which delivers an active compoundefficiently to the eye in such a way that the liquid vehicles issubsequently eliminated via evaporation. This is in sharp contrast tooily or perfluorinated eye drop vehicles which do easily not evaporateand thus form non-physiological residues at the site of administration,e.g. in the lacrimal sac.

Moreover, the invention provides a means of formulating non-aqueousophthalmic compositions which are microbiologically stable. This is dueto the fact that SFA's are not normally prone to microbialcontamination. Hence, it is possible to formulate preservative-freeophthalmic compositions which are better tolerable for many patients, inparticular patients suffering from an ophthalmic disease or condition.The same benefit is achieved when the suspensions are used forparenteral injection.

Preferably, the SFA-based suspensions of the invention are used toformulate active ingredients which are either poorly water-soluble orsensitive to hydrolytic degradation, or both. It is believed that theinvention is particularly useful if the active compound is selected frompoorly water-soluble drug substances which are otherwise challenging toformulate for ophthalmic or injectable use. As used herein, a compoundis poorly water-soluble if it exhibits a solubility falling into thedefinitions of “sparingly soluble”, “slightly soluble”, “very slightlysoluble”, or “practically insoluble” (according to Ph. Eur. 6th Ed.).Particularly preferred are active ingredients which are “very slightlysoluble” or “practically insoluble”. In another embodiment, it ispreferred that the active ingredient exhibits a water solubility of lessthan about 1 mg per mL, as measured at room temperature (between 15 and25° C.) and at neutral pH (pH 6.0 and pH 8.0).

Examples of suitable active ingredients include poorly solubleantibiotic agents such as ofloxacin, ciprofloxacin, levofloxacin,lomefloxacin, moxifloxacin, gentamycin, tobramycin, chloramphenicol,polymyxin B, neomycin, kanamycin, erythromycin, or fusidic acid; poorlysoluble antifungal agents such as amphotericin B; poorly solublecorticoids such as fluorometholone, prednisolone, or dexamethasone;poorly soluble non-steroidal anti-inflammatory agents such as ibuprofen,indometacine, or flurbiprofene; or poorly soluble antiviral agents suchas ganciclovir, to mention only a few of the potential drug candidates.

The active ingredient is incorporated in the form of suspended solidparticles. In a particular embodiment, the suspended particles largelyor exclusively consist of the active ingredient. In another embodiment,the active ingredient is associated with, or embedded in, a solidmaterial which also does not dissolve in the continuous liquid phase ofthe suspension.

The particle size of the dispersed phase is preferably below about 300μm, which means that most of the particles, e.g. at least about 90%thereof, have a size in this range. Which type of particle diameter isconsidered as particle size will depend on the method use for particlesize distribution, which in turn is selected to be appropriate for thetype of solid material and the approximate size range. For example,laser diffraction or dynamic light scattering (also known as photoncorrelation spectroscopy or quasi-elastic light scattering) areappropriate methods for determining particle sizes in the colloidal andlow micron range, whereas sedimentation analysis, sieve analysis orphotoanalysis may be selected for larger particle sizes.

In a further embodiment, at least about 90% of the suspended particleshave a size of not more than about 200 μm, in particular from about 0.2μm to about 200 μm, or from about 0.5 μm to about 150 μm, or from about1 μm to about 100 μm. Especially for ophthalmic administration, it mayalso be useful to select micronised material whose predominant particlesize is in the range from about 1 μm to about 20 μm, with mean (volumeaverage) particle sizes e.g. in the range from about 2 μm to about 15μm, as measured by laser diffraction, and in particular from about 2 μmto about 10 μm.

As mentioned, the advantageous effects of the invention are particularlyobvious when an active ingredient is selected which is poorlywater-soluble and/or sensitive to water, e.g. prone to hydrolyticdegradation. Especially in combination with such labile activeingredient it is recommended that the composition is substantially freeof water, perhaps except for the residual amounts of water which may beintroduced via the solid or liquid components. At the same time,water-free suspensions may also be useful in many other cases.

In contrast to some other suspensions known in prior art, theformulations of the invention require no surfactant, or only smallamounts of surfactant, for their physical stabilisation. This is asignificant advantage as surfactants have a substantial potential forirritation and local toxicity, especially when administered to the eyeor by injection. According to one of the preferred embodiments, thecompositions of the invention are substantially free of surfactant. In afurther embodiment, the total amount of surfactant or surfactants, ifmore than one surfactant is incorporated, is not more than about 10wt.-%, in particular not more than about 5 wt.-%, or preferably not morethan about 2 wt.-%, respectively. In further preferred embodiments, theamount is not more than about 1 wt.-%, or not more than about 0.5 wt.-%,respectively.

In this context, the SFA's as described herein, although they possesssome amphiphilic properties due to their chemical structure whichincludes fluorinated and non-fluorinated alkyl (or alkylene) groupscharacterised by different degrees of lipophilicity, are not understoodas being within the scope of surfactants.

The surfactants which are absent or only present in small amountsinclude non-ionic, cationic, anionic, and zwitterionic surfactants ascommonly used as excipients in various types of pharmaceuticalcompositions, e.g. as wetting agents, emulsifiers, dispersing agents,solubilisers and the like. Examples of surfactants which are consideredpotentially useful include tyloxapol, poloxamers such as Pluronic F68LFor Lutrol F68, Pluronic L-G2LF and Pluronic L62D, polysorbates such aspolysorbate 20 and polysorbate 80, polyoxyethylene castor oilderivatives, sorbitan esters, polyoxyl stearates, lecithins, purified orsynthetic phospholipids, and mixtures of two or more thereof.

The compositions of the invention may further comprise a non-fluorinatedorganic liquids, for example in order to modify the properties of theliquid vehicle, such as the viscosity. Such other liquid may be an oilselected from glyceride oils, liquid waxes, and liquid paraffin, or anorganic solvent exhibiting a high degree of biocompatibility, or amixture of more than one liquid excipients.

Examples of potentially useful oily excipients which may be used incombination with one or more SFA's include triglyceride oils (i.e.soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweetalmond oil), mineral oil (i.e. petrolatum and liquid paraffin), mediumchain triglycerides (MCT), oily fatty acids, isopropyl myristate, oilyfatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters,or any other oily substance which is physiologically tolerated by theeye.

Examples of potentially useful organic solvents include glycerol,propylene glycol, polyethylene glycol, and ethanol. However, theconcentration of the cosolvent should preferably be low relative to thatof the SFA or SFA mixture. If an organic solvent such as ethanol isused, it is recommendable to keep it below a level of approx 5 wt.-%.More preferably, the content of ethanol is from about 0.1 to about 2wt.-%, and most preferably not more than about 1 wt.-%.

The composition may of course comprise further pharmaceutical excipientsas required or useful. Potentially useful excipients include acids,bases, antioxidants, stabilisers, synergists, coloring agents,thickening agents, and—if required in a particular case—a preservative.

Furthermore, the invention provides a pharmaceutical kit comprising thecomposition as described above and a container holding the composition.Preferably, the container which contains the composition has adispensing means such as a dropping device adapted for topicallyadministering the composition to the eye of a patient. In one of thepreferred embodiments, the dispensing means is adapted to dispense thecomposition dropwise in volumes of less than about 30 μl per drop. Infurther embodiments, the dispensing means is adapted to dispense dropshaving a volume of less than about 20 μl, 15 μl, or 10 μl, respective.In particular, drop volumes of less than 10 μl are presently consideredvery useful in view of the limited holding capacity of one of thepreferred sites of administration, the front of the eye. For theavoidance of doubt, such small droplet sizes are primarily enabled bythe incorporation of the SFA (or SFA's) according to the invention, andcommon droppers for eye drops which normally deliver aqueous drops ofabout 30 to 60 μl are capable of dispensing much smaller drops ofSFA-based formulations.

The liquid suspensions of the invention may be prepared by conventionalmethods. In principle, the solid particles comprising the activeingredient may be dispersed in the liquid vehicle comprising the SFA.Alternatively, the particles may be precipitated in situ by addinga—typically organic—solution of the active ingredient (and, optionally,one or more solid excipients) under controlled conditions to theSFA-based vehicle.

The particle size of the dispersed phase may be adjusted before or afterthe particles are combined with the liquid vehicle. In one of thepreferred embodiments, particles of the active ingredient are providedwhich already have the appropriately selected particle size. Powdershaving such selected particle size may be obtained directly from thesynthesis of the respective compound by crystal engineering, or aftersynthesis by conventional grinding or milling methods using standardequipment such as a ball mill, hammer mill, roller mill, colloidal mill,jet mill, or the like. If the particle size is to be reduced afterpreparation of a suspension, ultrasonication as well as various types ofhomogenisers may be used, such as colloid mills or high pressurehomogenisers.

The following examples serve to illustrate the invention; however, theseare not to be understood as restricting the scope of the invention.

EXAMPLES Example 1

The droplet size of selected SFA's in terms of weight and volume ofdroplets from three droppers was determined and compared to that ofpurified water. The devices used for dispensing the droplets were (a) a2 mL Pasteur pipette (wall thickness 0.53 mm; external tip diameter:1.50 mm; length: 150 mm) made of glass, (b) a 20 G (0.9 mm×50 mm)injection needle, and (c) a dropper from a commercial eye drops product(Hylo-Vision). The droplet weights were measured at 25° C. using alaboratory balance; the volumes were calculated. Each test was performed10 times. The results of the experiments (mean values of droplet sizesand standard deviations) are shown in table 2.

TABLE 2 Glass pipette Injection needle Eye dropper Material mg μL mg μLmg μL Water 31.2 ± 1.4  31.3 ± 1.4  11.0 ± 0.9  11.1 ± 0.9  36.0 ± 2.236.1 ± 2.2 F4H5 6.0 ± 0.4 4.7 ± 0.3 2.6 ± 0.4 2.0 ± 0.3 12.4 ± 0.2  9.6± 0.2 F6H8 6.6 ± 0.6 5.0 ± 0.4 3.4 ± 0.2 2.5 ± 0.1 13.7 ± 0.4 10.3 ± 0.3

Table 2 shows that droplets of F4H5 and F6H8 are dramatically smallerand lighter than water droplets dispensed from the same device. Takinginto account the fact that SFA's have a high capacity to dissolve manyactive ingredients very well, it is concluded that SFA's are highlysuitable liquid vehicles for eye drops which are better retained by thelacrimal sac, produce little spill-over, and thus have a potential todeliver a dose more reliably and reproducibly to the eye thanconventional eye drop formulations.

Example 2

The physiological tolerability of F4H5 and of a mixture of 1 wt.-%ethanol in F4H5 was evaluated in an ex-vivo eye irritation test (EVEIT)using rabbit eyes taken from freshly sacrificed animals. The eyes werefastened in chambers coupled micropump systems which continuouslysupplied the eyes with cultivation medium (Minimal Essential Medium, MEMT031-05) without fetal calf serum. The vitality of the eyes wasmonitored by regularly measuring the concentration of lactate andglucose in the chamber eluate. The corneal surface of the eyes wasdamaged by abrasion, using a dental ceramic abrasive (638XF, Meisinger).For each eye, four lesions of 3.0 to 4.5 mm² were prepared.

To evaluate the effect of F4H5 and F4H5 with 1 wt.-% ethanol on thecornea, an amount of approx. 0.25 to 0.50 μl of the respective testsubstance was dropped onto the centre of a cornea once every hour over aperiod of 12 hours, followed by a 12 hour resting period in which thecornea was submersed in culture medium to simulate a closed lid during anight phase. In addition, an aqueous solution of hyaluronic acid (0.1wt.-%) was used as reference (hyaluronic acid is know to enhance therestoration of the corneal surface after damage), culture medium wasused as control, and aqueous benzalkonium chloride solution (0.01 wt.-%)was used as negative control. Each test was performed over a period of 3days. The effects were observed by optical coherence tomography (OCT),by digitally determining the dimensions of the lesions after stainingwith fluorescein, and finally by a histological evaluation of thecorneal epithelium and endothelium at the end of each experiment.

In result, it was found that in particular F4H5 was better toleratedthan culture medium, and that it exhibits a positive effect on thehealing of damaged cornea similar to that of hyaluronic acid. Even whencomprising 1 wt.-% of ethanol, F4H5 is tolerated very well by the eye.OCT imaging revealed no indication of penetration of F4H5 into thecornea.

In more detail, it was found that the lesions prepared by abrasionbecame smaller or larger over time depending on the liquid that wasadministered to the cornea. Substantial healing occurred when F4H5, F4H5with 1 wt.-% ethanol, or hyaluronic acid was used. In marked contrast,benzalkonium chloride administration lead to a rapid growth of thelesions eventually leading to a complete disintegration of the cornealepithelium. Culture medium had an intermediate effect. Tables 3 and 4shows the dimensions of the lesions [mm²] before and after the testswith the various test liquids and controls, respectively.

TABLE 3 F4H5 F4H5 + 1% EtOH Run 1 Run 2 Run 3 Run 1 Run 2 Initial size[mm²] 9.95 12.88 12.09 14.68 14.99 Final size [mm²] 0.19 1.01 0.06 0.302.26 Change [%] −98.1 −99.0 −99.5 −98.0 −84.9 *EtOH: ethanol

TABLE 4 HA MEM Run 1 Run 2 Run 3 Run 1 Run 2 Run 3 BAC Initial size[mm²] 13.22 16.03 14.87 15.5 15.57 13.11 16.05 Final size [mm²] 0.360.24 0.00 2.51 6.83 0.00 >60 Change [%] −97.3 −98.5 −100 −83.8 −56.1−100 ** *HA: hyaluronic acid; BAC: benzalkonium chloride; MEM: minimalessential medium ** Lesion essentially covered the complete cornealsurface

Morphological and histological evaluation revealed that the corneastreated with F4H5 or hyaluronic acid had not only healed very well, butwere also entirely clear at the end of the tests, with healthy andsmooth surface morphology. Eyes treated with F4H5 with 1 wt.-% ethanolshowed a healthy overall morphology, the corneas were clear and theepithelia revealed only very minor signs of damage remaining from thelesions. In contrast, some of the controls treated with culture mediumshowed significant surface roughness, and the eye treated withbenzalkonium chloride showed not only the complete disintegration of thecorneal epithelium, but also a major impairment of the complete corneaeven including the endothelium.

Example 3

In a similar set of experiments as described in Example 2, thephysiological tolerability of F6H8 and of a mixture of 1.0 wt.-% ethanolin F6H8 were evaluated in an ex-vivo eye irritation test (EVEIT). Again,minimal essential medium (MEM) was included as negative control,benzalkonium chloride solution (0.01%) as positive control, andhyaluronic acid solution (0.1%) as a reference.

In result, control treatment with MEM lead to a complete remission ofthe abrasions (starting size: 14.14 mm²) within 2 days, whereas thetreatment with BAC increased the lesions from 11.23 mm² to a completeepithelial loss affecting all of the corneal surface. In the case ofhyaluronic acid, the area of corneal damage started with 12.16 mm² andwas reduced within 3 days to only 0.32 mm² in a first set ofexperiments, representing a reduction by 97.4%. In a second set,complete healing was achieved with this reference compound. In twoseparate sets for each test, both F6H8 as well as the mixture of ethanol(1.0%) in F6H8 also lead to a complete remission of the corneal lesionsof 10.54 to 16.65 mm² in size after 2 or 3 days of exposure,respectively, indicating an excellent ophthalmic compatibility.

Example 4

The grinding jar of a laboratory-size planetary ball mill was filledwith 8 ml of a suspension of various amounts of crude ciprofloxacin inF6H8 or F4H5, respectively. The mixtures were processed until fine,homogeneous suspensions with particle sizes predominantly below 50 μmwere obtained. The densities of the suspensions were determined as 1.327g/cm³ (ciprofloxacin/F6H8; 3 mg/ml) and 1.286 g/cm³ (ciprofloxacin/F4H5;3 mg/ml), respectively.

The spreading behaviour of the ciprofloxacin/F6H8-suspension wasdetermined by placing an amount of 50 μL of the suspension onto a clean,plane glass plate. It was observed that the suspension spread evenly;almost the complete wetted area of the glass surface also exhibitedactive ingredient particles. In other words, not only the liquid phaseof the suspension shows an excellent spreading behaviour, but thesuspension as such, including the dispersed solid phase.

The dynamic viscosity of ciprofloxacin/F6H8-suspensions was determinedfor various concentrations of ciprofloxacin. In result, the viscositiesat concentrations of 0, 1, 3, and 5 mg/ml were all in the range fromabout 3.4 to 3.6 mPa·s; only at concentrations of 10 and 20 mg/ml, theviscosity increased moderately to 3.8 and 4.1 mPa·s, respectively,indicating that the suspension will be easily dispensable withconventional droppers or similar devices even at relatively highconcentrations of the active ingredient.

Example 5

In a similar manner as described in Example 4, suspensions were preparedfrom crude levofloxacin, ganciclovir sodium, chlorhexidine andN-octanoyl dopamine in F4H5 or F6H8 having various concentrations of theactive ingredients in the range from 1.5 mg/ml to 40 mg/ml wereprepared. The suspensions were physically stable. Those in which thedispersed phase settled or creamed over time were readily redispersibleby gentle shaking. Excellent spreading behaviour was observed, inparticular for the suspensions based on F6H8.

Example 6

A solution of 10 mg of dexamethasone in absolute ethanol was slowlydripped into 10 ml of F6H8 under stirring and at room temperature.Subsequently, the mixture was cooled with ice and ultrasonicated for 40seconds (Hielscher, UP400S, 100% amplitude). Next, the ethanol wasevaporated under vacuum using a rotary evaporator. A fine suspension wasobtained whose particle size distribution was determined by laserdiffraction (HELOS, Sympatec GmbH). In result, the volume mean diameter(VMD) was 12.20±0.17 m; the corresponding percentile diametersindicating the dimensions below which lie the diameters of 10%, 50% and90% of the particles, were 2.52±0.03 μm (X₁₀), 10.28±0.11 μm (X₅₀) and24.35±0.38 μm (X₉₀).

Example 7

The grinding jar (steel, volume: 25 ml) of a laboratory-size planetaryball mill (Retsch, PM100) was filled with 80 grinding balls (steel,diameter; 3 mm), 24 mg of crude ciprofloxacin and 8 ml of F6H8. Themixture was processed for 3 h at 480 rpm, during which the direction ofrotation was switched every 10 minutes. Thus a fine suspension wasobtained whose particle size distribution was determined by laserdiffraction (HELOS, Sympatec GmbH). The volume mean diameter (VMD) was11.85±0.24 μm, X₁₀ was 2.70±0.06 μm, X₅₀ was 9.16±0.15 μm, and X₉₀ wasdetermined as 25.05±0.55 μm.

As a control, a suspension of 24 mg of crude ciprofloxacin in 8 ml ofperfluorooctane (PFO) was prepared using the same procedure. Therespective particle size distribution parameters were 11.81±0.07 μm(VMD), 1.64±0.01 μm (X₁₀), 10.07±0.05 μm (X₅₀), and 24.11±0.11 μm (X₉₀).The particle size distributions of both suspensions are also depicted inFIG. 1.

The two suspensions showed a remarkably different physical stability andbehaviour upon vigorous shaking. While the suspension according to theinvention (comprising F6H8) remained finely dispersed and substantiallyhomogeneous for at least 30 minutes after shaking, the PFO-basedsuspension became visibly inhomogeneous within the first 60 secondsafter shaking, and the solid particles apparently aggregated and floatedas a distinct layer on the liquid phase starting from about 2 minutesafter shaking (see FIG. 3).

Example 8

In a similar procedure as in Example 7, suspensions of levofloxacin (40mg in 8 ml) in each of F6H6, F6H8 and perfluorooctane (PFO),respectively, were prepared, except that the processing time was 12hours for each batch. Again, fine suspensions were obtained whoseparticle distribution parameters are given in table 5 below. Theparticle size distributions of the suspensions are also depicted in FIG.2.

Again, the suspensions differed remarkably from each other with respectto their physical stability and behaviour upon vigorous shaking. Whilethe suspensions according to the invention (comprising F6H6 and F6H8)remained finely dispersed and substantially homogeneous for at least 30minutes after shaking, the PFO-based suspension became visiblyinhomogeneous within second. The solid particles in the PFO-basedsuspension aggregated rapidly and assembled as a distinct floating layeron the liquid phase starting from about 5 minutes after shaking (seeFIG. 4).

TABLE 5 Liquid phase X₁₀ [μm] X₅₀ [μm] X₉₀ [μm] VMD F6H8 1.33 ± 0.015.76 ± 0.02 12.75 ± 0.17 6.69 ± 0.04 F6H6 2.28 ± 0.02 8.41 ± 0.04 17.15± 0.16 9.22 ± 0.07 PFO 3.49 ± 0.13 10.24 ± 0.07  20.84 ± 0.19 11.35 ±0.10 

Example 9

In order to evaluate the biological activity of suspended activeingredients in SFA's, suspensions of ciprofloxacin, tobramycin, andgentamycin, each individually and separately suspended in F4H5 or F6H8,respectively, were prepared and tested in an agar diffusion testaccording to Clinical and Laboratory Standards Institute (CLSI).Commercially available standard filter paper disks loaded with 5 μg ofciprofloxacin were compared to filter paper disks soaked with 1.66 μL ofa suspension of ciprofloxacin (3 mg/mL) in F4H5 or F6H8, respectively.Similarly, standard filter paper disks loaded with 10 μg of tobramycinwere compared to disks soaked with 3.3 μL of a suspension of tobramycin(3 mg/mL) in F4H5 or F6H8, respectively; and standard filter paper disksloaded with 10 μg of gentamycin were compared to disks soaked with 3.3μL of a suspension of gentamycin (3 mg/mL) in F4H5 or F6H8,respectively. The disks were placed on agar culture plates (agar typeMH) innoculated with Staphylococcus aureus, Escherichia coli orPseudomonas aeruginosa, respectively, and incubated. In result, it wasfound that the inhibition zones around the disks differed substantiallybetween the various active compounds and also between test germs withinhibition zones ranging from 16 to 40 mm, whereas there was nosubstantial difference between the standard disks and the correspondingdisks loaded with the experimental suspensions of the same activecompound (inhibition zones mostly differing by about 2 or 3 mm only).Thus it is clear that the suspensions according to the invention retainthe biological activity of the incorporated drug substances.

The invention claimed is:
 1. A pharmaceutical composition in the form ofa suspension comprising a dispersed phase in a liquid continuous phasewherein: (a) the dispersed phase comprises solid particles of an activeingredient, said active ingredient is selected from the group consistingof antibiotic agents, antifungal agents, corticoid, non-steroidalanti-inflammatory agents, and antiviral agents, said active ingredientbeing present in a therapeutically effective amount, and (b) the liquidcontinuous phase comprises a liquid vehicle comprising a semifluorinatedalkane of formula RFRH, wherein RF is a linear perfluorinatedhydrocarbon segment with 3 to 10 carbon atoms, and wherein RH is alinear alkyl group with 3 to 10 carbon atoms; wherein the composition issubstantially free of water, and wherein the particles of the activeingredient have a volume mean diameter as measured by laser diffractionof not more than 15 μm.
 2. The composition of claim 1, wherein theparticles of the active ingredient have a volume mean diameter asmeasured by laser diffraction of about 2 to about 10 μm.
 3. Thecomposition of claim 1, wherein the active ingredient is an antibioticagent selected from ofloxacin, ciprofloxacin, levofloxacin,lomefloxacin, moxifloxacin, gentamycin, tobramycin, chloramphenicol,polymyxin B, neomycin, kanamycin, erythromycin, and fusidic acid.
 4. Thecomposition of claim 1, wherein the active ingredient is the antifungalagent amphotericin B.
 5. The composition of claim 1, wherein the activeingredient is a corticoid selected from fluorometholone, prednisolone,and dexamethasone.
 6. The composition of claim 1, wherein the activeingredient is an anti-inflammatory agent selected from ibuprofen,indomethacin, and flurbiprofen.
 7. The composition of claim 1, whereinthe active ingredient is the anti-viral agent ganciclovir.
 8. Thecomposition of claim 1, wherein the suspension remains substantiallyhomogenous and finely dispersed for at least 30 minutes after shaking.9. The composition of claim 1, being substantially free of a surfactant.10. The composition of claim 1, wherein the composition comprises atotal amount of surfactant of not more than about 5 wt.-%.
 11. Thecomposition of claim 1, wherein the active ingredient is a poorlywater-soluble drug substance and/or sensitive to hydrolytic degradation.12. The composition of claim 1, wherein the active ingredient exhibits awater solubility of less than about 1 mg per ml, as measured at roomtemperature and neutral pH.
 13. The composition of claim 1, wherein thesemifluorinated alkane is selected from F4H5 and F6H8.
 14. Thecomposition of claim 1, wherein the composition is adapted for topicalophthalmic administration to an eye of a patient.
 15. The composition ofclaim 1, wherein the semifluorinated alkane is selected from F4H5, F4H6,F6H6 and F6H8.
 16. A pharmaceutical composition in the form of asuspension comprising a dispersed phase in a liquid continuous phasewherein: (a) the dispersed phase comprises solid particles of an activeingredient, said active ingredient is selected from the group consistingof antibiotic agents, antifungal agents, corticoid, non-steroidalanti-inflammatory agents, and antiviral agents, said active ingredientbeing present in a therapeutically effective amount, and (b) the liquidcontinuous phase comprises a liquid vehicle comprising a semifluorinatedalkane of formula RFRH, wherein RF is a linear perfluorinatedhydrocarbon segment with 3 to 10 carbon atoms, and wherein RH is alinear alkyl group with 3 to 10 carbon atoms; wherein the composition issubstantially free of water, wherein the composition further comprises anon-fluorinated organic liquid, and wherein the particles of the activeingredient have a volume mean diameter as measured by laser diffractionof not more than 15 μm.
 17. The composition of claim 16, wherein thenon-fluorinated organic liquid is an oil or an organic solvent;optionally wherein the oil is selected from the group consisting of aglyceride oil, a liquid wax or a liquid paraffin.
 18. The composition ofclaim 16, wherein the active ingredient is an antibiotic agent selectedfrom ofloxacin, ciprofloxacin, levofloxacin, lomefloxacin, moxifloxacin,gentamycin, tobramycin, chloramphenicol, polymyxin B, neomycin,kanamycin, erythromycin, and fusidic acid; or a corticoid selected fromfluorometholone, prednisolone, and dexamethasone; or ananti-inflammatory agent selected from ibuprofen, indomethacin, andflurbiprofen; or the antifungal agent amphotericin B; or the anti-viralagent ganciclovir.
 19. The composition of claim 16, wherein theparticles of the active ingredient have a volume mean diameter asmeasured by laser diffraction of about 2 to about 10 μm.
 20. Thecomposition of claim 16, wherein the semifluorinated alkane is selectedfrom F4H5, F4H6, F6H6 and F6H8, or wherein the semifluorinated alkane isselected from F4H5 and F6H8.
 21. The composition of claim 1, wherein thesemifluorinated alkane has a refractive index in the range of 1.29 to1.35 at 20° C.
 22. The composition of claim 1, wherein thesemifluorinated alkane is selected from F4H4, F4H5, F4H6, F4H7, F4H8,F6H4, F6H6, F6H7, F6H8, F6H9, and F6H10.